Department of Cancer Biology, Wake Forest Baptist Comprehensive Cancer Center, Wake Forest Baptist Medical Center, Medical Center Blvd, Winston-Salem, North Carolina.
Nankai University School of Medicine, Tianjin, China.
Cancer Res. 2021 Jun 15;81(12):3358-3373. doi: 10.1158/0008-5472.CAN-21-0688. Epub 2021 Apr 14.
When recruited to promoters, histone 3 lysine 4 (H3K4) methyltransferases KMT2 (KMT2A-D) activate transcription by opening chromatin through H3K4 methylation. Here, we report that mutations occur frequently in non-small cell lung cancer (NSCLC) and are associated with high mutation loads and poor survival. KMT2C regulated DNA damage responses (DDR) through direct recruitment to DNA damage sites by Ago2 and small noncoding DNA damage response RNA, where it mediates H3K4 methylation, chromatin relaxation, secondary recruitment of DDR factors, and amplification of DDR signals along chromatin. Furthermore, by disrupting homologous recombination (HR)-mediated DNA repair, mutations sensitized NSCLC to Poly(ADP-ribose) polymerase inhibitors (PARPi), whose efficacy is unclear in NSCLC due to low mutation rates. These results demonstrate a novel, transcription-independent role of KMT2C in DDR and identify high-frequency mutations as much-needed biomarkers for PARPi therapies in NSCLC and other cancers with infrequent mutations. SIGNIFICANCE: This study uncovers a critical role for KMT2C in DDR via direct recruitment to DNA damage sites, identifying high-frequency mutations as biomarkers for response to PARP inhibition in cancer.
当招募到启动子时，组蛋白 3 赖氨酸 4（H3K4）甲基转移酶 KMT2（KMT2A-D）通过 H3K4 甲基化打开染色质来激活转录。在这里，我们报告说， 突变在非小细胞肺癌（NSCLC）中经常发生，并且与高突变负荷和不良预后相关。KMT2C 通过 Ago2 和小非编码 DNA 损伤反应 RNA 直接募集到 DNA 损伤部位来调节 DNA 损伤反应（DDR），在那里它介导 H3K4 甲基化、染色质松弛、DDR 因子的二次募集以及 DDR 信号沿着染色质的扩增。此外，通过破坏同源重组（HR）介导的 DNA 修复， 突变使 NSCLC 对聚（ADP-核糖）聚合酶抑制剂（PARPi）敏感，由于 NSCLC 中的 突变率低，PARPi 的疗效尚不清楚。这些结果表明 KMT2C 在 DDR 中具有新型的、转录独立的作用，并确定高频 突变作为 NSCLC 和其他 突变频率低的癌症中 PARPi 治疗的急需生物标志物。意义：本研究通过直接募集到 DNA 损伤部位，揭示了 KMT2C 在 DDR 中的关键作用，确定高频 突变作为癌症对 PARP 抑制反应的生物标志物。
